Project Summary Testicular cancer, although rare in the general population, represents around 60% of all cancers in young men aged 20-40 years. Its incidence has increased several-fold during the 20th century, but reasons for this are largely unknown. Established risk factors include cryptorchidism, Caucasian ethnicity as well as family history of testicular cancer and scientists strongly suspect that environmental exposures particularly during fetal development may play a role. The endocrine disruption hypothesis suggests that exposure to endocrine disrupting chemicals (EDCs) during fetal development disrupts normal reproductive organ development associated with long-term adverse reproductive effects, including testicular cancer. Despite heightened con- cern and tremendous scientific and public attention during the past 20 years, epidemiological data are still sparse. The conditions rarity in the population, long lag time between the sensitive period during fetal de- velopment and clinical appearance and lack of appropriate animal models for testicular cancer have hin- dered the understanding of the factors involved in the development of this cancer and few if any studies have quantified prenatal exposure to EDCs and were unable to address risk of testicular cancer from fetal exposures. Therefore, there is a need for epidemiological based research with reliable data based on expo- sure assessment quantified in biological prenatal samples, which are considered the gold standard. The objective of the present proposal is to address this knowledge gap using a cohort of 128,702 women who provided blood and amniotic fluid samples during their pregnancies in the period 1976-96. By registry link- age within highly reliable national population and disease registries for ascertainment for outcome/poten- tial confounders we will identify all sons diagnosed with testicular cancer (including sub-types) and match each of these at the time of their diagnosis to two control sons (n=550 sons) using risk set sampling. Levels of EDCs including DDT, DDE and other organochlorine pesticides, PCBs, PBDEs, PFAS, phthalates and triclosan will be quantified in prenatal biosamples from mothers. This study is important in relation to the overall mission of the National Institute of Environmental Health Sciences and will contribute substan- tially to the weight of the evidence in support of or against the fetal programing hypothesis with respect to testicular cancer and environmental EDCs. No similar research has been carried out in the US. Elucidating the association between relevant environmental EDCs and testicular cancer may reveal potentially modifia- ble risk factors, leading to guidelines for pregnant women so they can take sensible measures to reduce their own exposures.